Use of gaboxadol in the treatment of tinnitus

ABSTRACT

Methods of treating tinnitus with gaboxadol or a pharmaceutically acceptable salt thereof are provided. The methods provide therapeutic compositions that may be used to improve one or more symptoms of tinnitus.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 15/873,425, filed Jan. 17, 2018, which claimsbenefit of and priority to U.S. Provisional Application No. 62/454,280,filed Feb. 3, 2017; U.S. Provisional Application No. 62/530,528, filedJul. 10, 2017; and U.S. Provisional Application No. 62/536,669, filedJul. 25, 2017 and which are incorporated herein by reference in theirrespective entireties.

TECHNICAL FIELD

Methods of treating tinnitus.

BACKGROUND

Tinnitus is characterized by an auditory sensation in the absence ofexternal sound. In many cases tinnitus is subjectively perceptual, i.e.,only the subject can perceive symptoms. Symptoms of tinnitus includeringing, roaring, static, buzzing, hissing and whistling in one or bothears. The noise may be intermittent or continuous. According to theNational Institute on Deafness and other Communication Disorders (NIDCD)approximately 10 percent of the US adult population, or about 25 millionAmericans, have experienced some degree of tinnitus. According to theAmerican Tinnitus Association, 20 million of these sufferers strugglewith burdensome chronic tinnitus, while 2 million have extreme anddebilitating cases. Severe tinnitus can lead to depression and othermental health challenges that severely affect the patient and thepatient's family members. Therapies such as masking, sound therapy,electrical stimulation, and drugs have shown some benefit.Unfortunately, these treatments may be insufficient and many patientscontinue to suffer with tinnitus. Therefore, treatment of tinnitusremains a significant need.

Gaboxadol (4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridine-3-ol) (THIP)) isdescribed in EP Patent No. 0000338 and in EP Patent No. 0840601, U.S.Pat. Nos. 4,278,676, 4,362,731, 4,353,910, and WO 2005/094820. Gaboxadolis a selective GABA_(A) receptor agonist with a preference for δ-subunitcontaining GABAA receptors. In the early 1980s gaboxadol was the subjectof a series of pilot studies that tested its efficacy as an analgesicand anxiolytic, as well as a treatment for tardive dyskinesia,Huntington's disease, Alzheimer's disease, and spasticity. In the 1990sgaboxadol moved into late stage development for the treatment ofinsomnia. The development was discontinued after the compound failed toshow significant effects in sleep onset and sleep maintenance in athree-month efficacy study. Additionally, patients with a history ofdrug abuse who received gaboxadol experienced a steep increase inpsychiatric adverse events.

Although gaboxadol has been suggested for treatment of tinnitus, recentresearch indicates that gaboxadol GABAA mediated tonic inhibition inauditory thalamus/medial geniculate body (MGB) may cause significanttinnitus related increases contralateral to sound exposure. See, e.g.,Sametsky et al., Journal of Neuroscience, (Jun. 24, 2015)35(25):9369-9380.

SUMMARY

Methods of treating tinnitus described herein include administering to apatient in need thereof about 0.05 mg to about 30 mg gaboxadol or apharmaceutically acceptable salt thereof wherein the method providesimprovement in tinnitus. Methods of treating tinnitus described hereininclude administering to a patient in need thereof about 0.05 mg toabout 30 mg gaboxadol or a pharmaceutically acceptable salt thereofwherein the method provides improvement in one or more symptoms oftinnitus. Methods of treating tinnitus described herein includeadministering to a patient in need thereof about 0.05 mg to about 30 mggaboxadol or a pharmaceutically acceptable salt thereof wherein themethod provides improvement in tinnitus the next day. Methods oftreating tinnitus described herein include administering to a patient inneed thereof about 0.05 mg to about 30 mg gaboxadol or apharmaceutically acceptable salt thereof wherein the method providesimprovement in the patient for more than 6 hours after administration tothe patient. Methods of treating tinnitus are described herein whichinclude administering to a patient in need thereof gaboxadol or apharmaceutically acceptable salt thereof wherein the method provides anin vivo plasma profile including a C_(max) less than about 400 ng/ml andwherein the method provides improvement in the patient for more than 6hours after administration of the gaboxadol or a pharmaceuticallyacceptable salt thereof. Methods of treating tinnitus are describedherein which include administering to a patient in need thereofgaboxadol or a pharmaceutically acceptable salt thereof wherein themethod provides an in vivo plasma profile comprising a AUC₆₋₁₂ of lessthan about 900 ng·hr/ml and wherein the method provides improvement inthe patient for more than 6 hours after administration of the gaboxadolor a pharmaceutically acceptable salt thereof. Methods of treatingtinnitus are described herein which include administering to a patientin need thereof a first pharmaceutical composition comprising gaboxadolor a pharmaceutically acceptable salt thereof and a secondpharmaceutical composition comprising gaboxadol or a pharmaceuticallyacceptable salt thereof wherein the second pharmaceutical compositionprovides an in vivo plasma profile comprising a mean AUC_(0-∞) of atleast 20% less than the first pharmaceutical composition.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the arithmetic mean plasma concentration-time profiles ofgaboxadol following single oral doses (2.5, 5, 10, 15, and 20 mg) asdescribed in Example 1 with horizontal lines Δ indicating the changebetween 6 and 12 hours.

FIG. 2 shows the arithmetic mean plasma concentration-time profiles ofgaboxadol following single oral doses (2.5, 5, 10, 15, and 20 mg) asdescribed in Example 1.

FIG. 3 schematically illustrates treatment of three groups over aproposed 12 week course of treatment: 1) single evening dose 2) morningand evening dose and 3) placebo.

DETAILED DESCRIPTION

Described herein are methods of treating tinnitus with gaboxadol or apharmaceutically acceptable salt thereof. Many pharmaceutical productsare administered as a fixed dose, at regular intervals, to achievetherapeutic efficacy. Its duration of action is reflected by its plasmahalf-life. Gaboxadol is a selective GABAA receptor agonist with arelatively short half-life (t½=1.5 h). Since efficacy is often dependenton sufficient exposure within the central nervous system administrationof CNS drugs with a short half-life may require frequent maintenancedosing. Advantageously disclosed herein are methods of treating tinnitusby administration of gaboxadol or a pharmaceutically acceptable saltthereof. For example, in embodiments, methods of treating tinnitus areprovided which include administering to a patient in need thereof apharmaceutical composition including about 0.05 mg to about 30 mggaboxadol or a pharmaceutically acceptable salt thereof wherein thecomposition provides improvement for more than 6 hours afteradministration to the patient.

Methods of treating tinnitus described herein include administering to apatient in need thereof about 0.05 mg to about 30 mg gaboxadol or apharmaceutically acceptable salt thereof wherein the method providesimprovement in one or more symptoms of tinnitus. Methods of treatingtinnitus described herein include administering to a patient in needthereof about 0.05 mg to about 30 mg gaboxadol or a pharmaceuticallyacceptable salt thereof wherein the method provides improvement intinnitus the next day. Methods of treating tinnitus described hereininclude administering to a patient in need thereof about 0.05 mg toabout 30 mg gaboxadol or a pharmaceutically acceptable salt thereofwherein the method provides improvement in the patient for more than 6hours after administration to the patient. Methods of treating tinnitusare described herein which include administering to a patient in needthereof gaboxadol or a pharmaceutically acceptable salt thereof whereinthe method provides an in vivo plasma profile including a C_(max) lessthan about 400 ng/ml and wherein the method provides improvement in thepatient for more than 6 hours after administration of the gaboxadol or apharmaceutically acceptable salt thereof. Methods of treating tinnitusare described herein which include administering to a patient in needthereof gaboxadol or a pharmaceutically acceptable salt thereof whereinthe method provides an in vivo plasma profile comprising a AUC₆₋₁₂ ofless than about 900 ng ng□hr/ml hr/ml and wherein the method providesimprovement in the patient for more than 6 hours after administration ofthe gaboxadol or a pharmaceutically acceptable salt thereof. Methods oftreating tinnitus are described herein which include administering to apatient in need thereof a first pharmaceutical composition comprisinggaboxadol or a pharmaceutically acceptable salt thereof and a secondpharmaceutical composition comprising gaboxadol or a pharmaceuticallyacceptable salt thereof wherein the second pharmaceutical compositionprovides an in vivo plasma profile comprising a mean AUC_(0-∞) of atleast 20% less than the first pharmaceutical composition.

Embodiments described herein provide that a patient in need thereof isadministered a pharmaceutical composition including gaboxadol or apharmaceutically acceptable salt thereof. Gaboxadol or pharmaceuticallyacceptable salt thereof may be provided as an acid addition salt, azwitter ion hydrate, zwitter ion anhydrate, hydrochloride orhydrobromide salt, or in the form of the zwitter ion monohydrate. Acidaddition salts, include but are not limited to, maleic, fumaric,benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic,methanesulfonic, ethane-di sulfonic, acetic, propionic, tartaric,salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic,citraconic, aspartic, stearic, palmitic, itaconic, glycolic,p-amino-benzoic, glutamic, benzene sulfonic or theophylline acetic acidaddition salts, as well as the 8-halotheophyllines, for example8-bromo-theophylline. In other suitable embodiments, inorganic acidaddition salts, including but not limited to, hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric or nitric acid addition salts may beused.

In embodiments, gaboxadol is provided as gaboxadol monohydrate. Oneskilled in the art will readily understand that the amounts of activeingredient in a pharmaceutical composition will depend on the form ofgaboxadol provided. For example, pharmaceutical compositions ofincluding 5.0, 10.0, or 15.0 mg gaboxadol correspond to 5.6, 11.3, or16.9 mg gaboxadol monohydrate.

In embodiments, gaboxadol is crystalline, such as the crystallinehydrochloric acid salt, the crystalline hydrobromic acid salt, or thecrystalline zwitter ion monohydrate. In embodiments, gaboxadol isprovided as a crystalline monohydrate.

Deuteration of pharmaceuticals to improve pharmacokinetics (PK),pharmacodynamics (PD), and toxicity profiles, has been demonstratedpreviously with some classes of drugs. Accordingly the use of deuteriumenriched gaboxadol is contemplated and within the scope of the methodsand compositions described herein. Deuterium can be incorporated in anyposition in replace of hydrogen synthetically, according to thesynthetic procedures known in the art. For example, deuterium may beincorporated to various positions having an exchangeable proton, such asthe amine N—H, via proton-deuterium equilibrium exchange. Thus,deuterium may be incorporated selectively or non-selectively throughmethods known in the art to provide deuterium enriched gaboxadol. SeeJournal of Labeled Compounds and Radiopharmaceuticals 19(5) 689-702(1982).

Deuterium enriched gaboxadol may be described by the percentage ofincorporation of deuterium at a given position in the molecule in theplace of hydrogen. For example, deuterium enrichment of 1% at a givenposition means that 1% of molecules in a given sample contain deuteriumat that specified position. The deuterium enrichment can be determinedusing conventional analytical methods, such as mass spectrometry andnuclear magnetic resonance spectroscopy. In embodiments deuteriumenriched gaboxadol means that the specified position is enriched withdeuterium above the naturally occurring distribution (i.e., above about.0156%). In embodiments deuterium enrichment is no less than about 1%, noless than about 5%, no less than about 10%, no less than about 20%, noless than about 50%, no less than about 70%, no less than about 80%, noless than about 90%, or no less than about 98% of deuterium at aspecified position.

In embodiments, methods of treating tinnitus include administering to apatient in need thereof a pharmaceutical composition including about0.05 mg to about 30 mg gaboxadol or a pharmaceutically acceptable saltthereof.

In embodiments, the pharmaceutical compositions include 0.1 mg to 25 mg,0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.5 mg to 25 mg, 0.5 mg to 20 mg, 0.5to 15 mg, 1 mg to 25 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1.5 mg to 25 mg,1.5 mg to 20 mg, 1.5 mg to 15 mg, 2 mg to 25 mg, 2 mg to 20 mg, 2 mg to15 mg, 2.5 mg to 25 mg, 2.5 mg to 20 mg, 2.5 mg to 15 mg, 3 mg to 25 mg,3 mg to 20 mg, 3 mg to 15 mg gaboxadol or a pharmaceutically acceptablesalt thereof.

In embodiments, the pharmaceutical compositions include 5 mg to 20 mg, 5mg to 10 mg, 4 mg to 6 mg, 6 mg to 8 mg, 8 mg to 10 mg, 10 mg to 12 mg,12 mg to 14 mg, 14 mg to 16 mg, 16 mg to 18 mg, or 18 mg to 20 mggaboxadol or a pharmaceutically acceptable salt thereof.

In embodiments, the pharmaceutical compositions include 0.1 mg, 0.25 mg,0.5 mg, 1 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7 mg, 7.5 mg, 10 mg, 12.5 mg, 15mg, 17.5 mg, 20 mg gaboxadol or a pharmaceutically acceptable saltthereof or amounts that are multiples of such doses. In embodiments, thepharmaceutical compositions include 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg,or 20 mg gaboxadol or a pharmaceutically acceptable salt thereof.

Pharmaceutical compositions herein may be provided with immediaterelease, delayed release, extended release, or modified releaseprofiles. In embodiments, pharmaceutical compositions with differentdrug release profiles may be combined to create a two phase orthree-phase release profile. For example, pharmaceutical compositionsmay be provided with an immediate release and an extended releaseprofile.

In embodiments, pharmaceutical compositions may be provided with anextended release and delayed release profile. Such composition may beprovided as pulsatile formulations, multilayer tablets, or capsulescontaining tablets, beads, granules, etc. Compositions may be preparedusing a pharmaceutically acceptable “carrier” composed of materials thatare considered safe and effective. The “carrier” includes all componentspresent in the pharmaceutical formulation other than the activeingredient or ingredients. The term “carrier” includes, but is notlimited to, diluents, binders, lubricants, disintegrants, fillers, andcoating compositions.

In embodiments, the pharmaceutical compositions described herein areadministered once, twice, or three times daily, or every other day. Inembodiments, a pharmaceutical composition described herein is providedto the patient in the evening. In embodiments, a pharmaceuticalcomposition described herein is provided to the patient once in theevening and once in the morning. In embodiments, the total amount ofgaboxadol or a pharmaceutically acceptable salt thereof administered toa subject in a 24-hour period is 1 mg to 30 mg. In embodiments, thetotal amount of gaboxadol or a pharmaceutically acceptable salt thereofadministered to a subject in a 24-hour period is 1 mg to 20 mg. Inembodiments, the total amount of gaboxadol or a pharmaceuticallyacceptable salt thereof administered to a subject in a 24-hour period is5 mg, 10 mg, or 15 mg. In embodiments, the total amount of gaboxadol ora pharmaceutically acceptable salt thereof administered to a subject ina 24-hour period is 20 mg.

In embodiments, provided herein are methods of treating tinnitusincluding administering to a patient in need thereof a pharmaceuticalcomposition including gaboxadol or a pharmaceutically acceptable saltthereof wherein the composition provides improvement in at least onesymptom of the tinnitus. Symptoms may include, but are not limited to,ringing, roaring, static, buzzing, hissing, whooshing, cricket noises,jackhammer noises and/or whistling in one or both ears. The symptoms maybe intermittent or continuous. Improvement in tinnitus symptoms throughadministration of gaboxadol is surprising in view of Sametsky et al.,supra.

In embodiments, provided herein are methods of treating tinnitusincluding administering to a patient in need thereof a pharmaceuticalcomposition including gaboxadol or a pharmaceutically acceptable saltthereof wherein the composition provides improvement of at least onetinnitus symptom for more than 4 hours after administration of thepharmaceutical composition to the patient. In embodiments, theimprovement of at least one tinnitus symptom for more than 6 hours afteradministration of the pharmaceutical composition to the patient isprovided in accordance with the present disclosure. In embodiments,improvement of at least one tinnitus symptom for more than, e.g., 8hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, or 24 hoursafter administration of the pharmaceutical composition to the patient isprovided in accordance with the present disclosure. In embodiments,improvement in at least one tinnitus symptom for at least e.g., 8 hours,10 hours, 12 hours, 15 hours, 18 hours, 20 hours, or 24 hours afteradministration of the pharmaceutical composition to the patient isprovided in accordance with the present disclosure. In embodiments,improvement in at least one tinnitus symptom for 12 hours afteradministration of the pharmaceutical composition to the patient isprovided in accordance with the present disclosure.

In embodiments, provided herein methods of treating tinnitus includingadministering to a patient in need thereof a pharmaceutical compositionincluding gaboxadol or a pharmaceutically acceptable salt thereofwherein the composition provides improvement in tinnitus the next day.

FIG. 1 shows the arithmetic mean plasma concentration-time profiles ofgaboxadol following single oral doses (2.5, 5, 10, 15, and 20 mg)(see,Example 1, below) with horizontal lines Δ indicating the change between6 and 12 hours. In embodiments, provided herein are methods of treatingtinnitus including administering to a patient in need thereof about 0.05mg to about 30 mg gaboxadol or a pharmaceutically acceptable saltthereof which provides an in vivo plasma profile, wherein the in vivoplasma profile of the patient 6 hours after administration of thegaboxadol or pharmaceutically acceptable salt thereof is reduced by morethan 50% and the method provides improvement in the patient for morethan 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration.In embodiments, provided herein are methods of treating tinnitusincluding administering to a patient in need thereof about 0.05 mg toabout 30 mg gaboxadol or a pharmaceutically acceptable salt thereofwhich provides an in vivo plasma profile, wherein the in vivo plasmaprofile of the patient 6 hours after administration of the gaboxadol orpharmaceutically acceptable salt thereof is reduced by more than 55% andthe method provides improvement in the patient for more than 6, 8, 10,12, 14, 16, 18, 20, 22 or 24 hours after administration. In embodiments,provided herein are methods of treating tinnitus including administeringto a patient in need thereof about 0.05 mg to about 30 mg gaboxadol or apharmaceutically acceptable salt thereof which provides an in vivoplasma profile, wherein the in vivo plasma profile of the patient 6hours after administration of the gaboxadol or pharmaceuticallyacceptable salt thereof is reduced by more than 60% and the methodprovides improvement in the patient for more than 6, 8, 10, 12, 14, 16,18, 20, 22 or 24 hours after administration. In embodiments, providedherein are methods of treating tinnitus including administering to apatient in need thereof about 0.05 mg to about 30 mg gaboxadol or apharmaceutically acceptable salt thereof which provides an in vivoplasma profile, wherein the in vivo plasma profile of the patient 6hours after administration of the gaboxadol or pharmaceuticallyacceptable salt thereof is reduced by more than 65% and the methodprovides improvement in the patient for more than 6, 8, 10, 12, 14, 16,18, 20, 22 or 24 hours after administration. In embodiments, providedherein are methods of treating tinnitus including administering to apatient in need thereof about 0.05 mg to about 30 mg gaboxadol or apharmaceutically acceptable salt thereof which provides an in vivoplasma profile, wherein the in vivo plasma profile of the patient 6hours after administration of the gaboxadol or pharmaceuticallyacceptable salt thereof is reduced by more than 70% and the methodprovides improvement in the patient for more than 6, 8, 10, 12, 14, 16,18, 20, 22 or 24 hours after administration. In embodiments, providedherein are methods of treating tinnitus including administering to apatient in need thereof about 0.05 mg to about 30 mg gaboxadol or apharmaceutically acceptable salt thereof which provides an in vivoplasma profile, wherein the in vivo plasma profile of the patient 6hours after administration of the gaboxadol or pharmaceuticallyacceptable salt thereof is reduced by more than 75% and the methodprovides improvement in the patient for more than 6, 8, 10, 12, 14, 16,18, 20, 22 or 24 hours after administration.

In embodiments, provided herein are methods of treating tinnitus whereinthe amount of gaboxadol or pharmaceutically acceptable salt thereofwithin the patient about 4 hours after administration of thepharmaceutical composition is less than about 75% of the administereddose. In embodiments, provided herein are methods wherein the amount ofgaboxadol or pharmaceutically acceptable salt thereof within the patientabout, e.g., 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, or 20 hoursafter administration of the pharmaceutical composition is less thanabout 75%.

In embodiments, provided herein are methods of treating tinnitus whereinthe amount of gaboxadol or pharmaceutically acceptable salt thereofwithin the patient about 4 hours after administration of thepharmaceutical composition is less than about 80% of the administereddose. In embodiments, provided herein are methods wherein the amount ofgaboxadol or pharmaceutically acceptable salt thereof within the patientabout, e.g., 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, or 20 hoursafter administration of the pharmaceutical composition is less thanabout 80% of the administered dose.

In embodiments, provided herein are methods of treating tinnitus whereinthe amount of gaboxadol or pharmaceutically acceptable salt thereofwithin the patient about 4 hours after administration of thepharmaceutical composition is between about 65% to about 85% of theadministered dose. In embodiments, the amount of gaboxadol orpharmaceutically acceptable salt thereof within the patient after about,e.g., 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, or 20 hours afteradministration of the pharmaceutical composition is between about 65% toabout 85% of the administered dose.

In embodiments, provided herein are methods of treating tinnitusincluding administering to a patient in need thereof a pharmaceuticalcomposition including gaboxadol or a pharmaceutically acceptable saltthereof wherein the composition provides an in vivo plasma concentration6 hours after administration which is less than 75% of the administereddose and provides improvement in the patient for more than 6, 8, 10, 12,14, 16, 18, 20, 22 or 24 hours after administration. In embodiments,provided herein are methods of treating tinnitus including administeringto a patient in need thereof a pharmaceutical composition includinggaboxadol or a pharmaceutically acceptable salt thereof wherein thecomposition provides an in vivo plasma concentration 6 hours afteradministration which is less than 80% of the administered dose andprovides improvement in the patient for more than 6, 8, 10, 12, 14, 16,18, 20, 22 or 24 hours after administration. In embodiments, providedherein are methods of treating tinnitus including administering to apatient in need thereof a pharmaceutical composition including gaboxadolor a pharmaceutically acceptable salt thereof wherein the compositionprovides an in vivo plasma concentration 6 hours after administrationwhich is less than 85% of the administered dose and provides improvementin the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24hours after administration. In embodiments, provided herein are methodsof treating tinnitus including administering to a patient in needthereof a pharmaceutical composition including gaboxadol or apharmaceutically acceptable salt thereof wherein the compositionprovides an in vivo plasma concentration 6 hours after administrationwhich is less than 90% of the administered dose and provides improvementin the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24hours after administration. In embodiments, provided herein are methodsof treating tinnitus including administering to a patient in needthereof a pharmaceutical composition including gaboxadol or apharmaceutically acceptable salt thereof wherein the compositionprovides an in vivo plasma concentration 6 hours after administrationwhich is less than 95% of the administered dose and provides improvementin the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24hours after administration. In embodiments, provided herein are methodsof treating tinnitus including administering to a patient in needthereof a pharmaceutical composition including gaboxadol or apharmaceutically acceptable salt thereof wherein the compositionprovides an in vivo plasma concentration 6 hours after administrationwhich is less than 100% of the administered dose and providesimprovement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20,22 or 24 hours after administration.

In embodiments, provided herein are methods of treating tinnitusincluding administering to a patient in need thereof a pharmaceuticalcomposition including gaboxadol or a pharmaceutically acceptable saltthereof wherein the composition provides an in vivo plasma profilehaving a C_(max) less than about 500 ng/ml. In embodiments, thecomposition provides improvement for more than 6 hours afteradministration to the patient.

In embodiments, the composition provides an in vivo plasma profilehaving a C_(max) less than about, e.g., 450 ng/ml, 400 ng/ml 350 ng/ml,or 300 ng/ml and wherein the composition provides improvement in one ormore symptoms of tinnitus a day after administration. In embodiments,the composition provides an in vivo plasma profile having a C_(max) lessthan about, e.g., 250 ng/ml, 200 ng/ml 150 ng/ml, or 100 ng/ml andwherein the composition provides improvement in one or more symptoms oftinnitus a day after administration.

In embodiments, provided herein are methods of treating tinnitusincluding administering to a patient in need thereof a pharmaceuticalcomposition including gaboxadol or a pharmaceutically acceptable saltthereof wherein the composition provides an in vivo plasma profilehaving a AUC_(0-∞) of less than about 900 ng·hr/ml. In embodiments, thecomposition provides improvement in one or more symptoms of tinnitus aday after administration. In embodiments, the compositions provide an invivo plasma profile having a AUC_(0-∞) of less than about, e.g., 850ng·hr/ml, 800 ng·hr/ml, 750 ng·hr/ml, or 700 ng·hr/ml and wherein thecomposition provides improvement in one or more symptoms of tinnitus aday after administration. In embodiments, the composition providesimprovement in one or more tinnitus symptoms for more than 6 hours afteradministration.

In embodiments, provided herein are methods of treating tinnitusincluding administering to a patient in need thereof a pharmaceuticalcomposition including gaboxadol or a pharmaceutically acceptable saltthereof wherein the composition provides an in vivo plasma profilehaving a AUC_(0-∞) of less than about, e.g., 650 ng·hr/ml, 600 ng·hr/ml,550 ng·hr/ml, 500 ng·hr/ml, or 450 ng·hr/ml. In embodiments, wherein thecomposition provides an in vivo plasma profile having a AUC_(0-∞) ofless than about, e.g., 400 ng·hr/ml, 350 ng·hr/ml, 300 ng·hr/ml, 250ng·hr/ml, or 200 ng·hr/ml. In embodiments, the composition provides anin vivo plasma profile having a AUC_(0-∞) of less than about, e.g., 150ng·hr/ml, 100 ng·hr/ml, 75 ng·hr/ml, or 50 ng·hr/ml. In embodiments, thecomposition provides improvement symptoms of tinnitus for more than,e.g., 4 hours, 6 hours, 8 hours, 10 hours, or 12 hours, afteradministration of the composition to the patient.

In embodiments, provided herein are methods of treating tinnitusincluding administering to a patient in need thereof an amount ofgaboxadol or a pharmaceutically acceptable salt thereof which providesan in vivo plasma profile having a AUC₆₋₁₂ which is less than 75% of theC_(max) and provides improvement in the patient for more than 6, 8, 10,12, 14, 16, 18, 20, 22 or 24 hours after administration. In embodiments,provided herein are methods of treating tinnitus including administeringto a patient in need thereof an amount of gaboxadol or apharmaceutically acceptable salt thereof which provides an in vivoplasma profile having a AUC₆₋₁₂ which is less than 80% of the C_(max)and provides improvement in the patient for more than 6, 8, 10, 12, 14,16, 18, 20, 22 or 24 hours after administration. In embodiments,provided herein are methods of treating tinnitus including administeringto a patient in need thereof an amount of gaboxadol or apharmaceutically acceptable salt thereof which provides an in vivoplasma profile having a AUC₆₋₁₂ which is less than 85% of the C_(max)and provides improvement in the patient for more than 6, 8, 10, 12, 14,16, 18, 20, 22 or 24 hours after administration. In embodiments,provided herein are methods of treating tinnitus including administeringto a patient in need thereof an amount of gaboxadol or apharmaceutically acceptable salt thereof which provides an in vivoplasma profile having a AUC₆₋₁₂ which is less than 90% of the C_(max)and provides improvement in the patient for more than 6, 8, 10, 12, 14,16, 18, 20, 22 or 24 hours after administration. In embodiments,provided herein are methods of treating tinnitus including administeringto a patient in need thereof an amount of gaboxadol or apharmaceutically acceptable salt thereof which provides an in vivoplasma profile having a AUC₆₋₁₂ which is less than 95% of the C_(max)and provides improvement in the patient for more than 6, 8, 10, 12, 14,16, 18, 20, 22 or 24 hours after administration. In embodiments,provided herein are methods of treating tinnitus including administeringto a patient in need thereof an amount of gaboxadol or apharmaceutically acceptable salt thereof which provides an in vivoplasma profile having a AUC₆₋₁₂ which is less than 100% of the C_(max)and provides improvement in the patient for more than 6, 8, 10, 12, 14,16, 18, 20, 22 or 24 hours after administration.

In embodiments, provided herein are methods of treating tinnitusincluding administering to a patient in need thereof a pharmaceuticalcomposition including gaboxadol or a pharmaceutically acceptable saltthereof wherein the composition provides an in vivo plasma profilehaving a AUC₆₋₁₂ which is less than 75% of the C_(max) and providesimprovement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20,22 or 24 hours after administration. In embodiments, provided herein aremethods of treating tinnitus including administering to a patient inneed thereof a pharmaceutical composition including gaboxadol or apharmaceutically acceptable salt thereof wherein the compositionprovides an in vivo plasma profile having a AUC₆₋₁₂ which is less than80% of the C_(max) and provides improvement in the patient for more than6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration. Inembodiments, provided herein are methods of treating tinnitus includingadministering to a patient in need thereof a pharmaceutical compositionincluding gaboxadol or a pharmaceutically acceptable salt thereofwherein the composition provides an in vivo plasma profile having aAUC₆₋₁₂ which is less than 85% of the C_(max) and provides improvementin the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24hours after administration. In embodiments, provided herein are methodsof treating tinnitus including administering to a patient in needthereof a pharmaceutical composition including gaboxadol or apharmaceutically acceptable salt thereof wherein the compositionprovides an in vivo plasma profile having a AUC₆₋₁₂ which is less than90% of the C_(max) and provides improvement in the patient for more than6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration. Inembodiments, provided herein are methods of treating tinnitus includingadministering to a patient in need thereof a pharmaceutical compositionincluding gaboxadol or a pharmaceutically acceptable salt thereofwherein the composition provides an in vivo plasma profile having aAUC₆₋₁₂ which is less than 95% of the C_(max) and provides improvementin the patient for more than 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24hours after administration. In embodiments, provided herein are methodsof treating tinnitus including administering to a patient in needthereof a pharmaceutical composition including gaboxadol or apharmaceutically acceptable salt thereof wherein the compositionprovides an in vivo plasma profile having a AUC₆₋₁₂ which is less than100% of the C_(max) and provides improvement in the patient for morethan 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration.

In embodiments, provided herein are methods of treating tinnitusincluding administering to a patient in need thereof a pharmaceuticalcomposition including gaboxadol or a pharmaceutically acceptable saltthereof wherein the composition provides an in vivo plasma profilehaving a AUC₆₋₁₂ which is less than 75% of the administered dose andprovides improvement in the patient for more than 6, 8, 10, 12, 14, 16,18, 20, 22 or 24 hours after administration. In embodiments, providedherein are methods of treating tinnitus including administering to apatient in need thereof a pharmaceutical composition including gaboxadolor a pharmaceutically acceptable salt thereof wherein the compositionprovides an in vivo plasma profile having a AUC₆₋₁₂ which is less than80% of the administered dose and provides improvement in the patient formore than 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours afteradministration. In embodiments, provided herein are methods of treatingtinnitus including administering to a patient in need thereof apharmaceutical composition including gaboxadol or a pharmaceuticallyacceptable salt thereof wherein the composition provides an in vivoplasma profile having a AUC₆₋₁₂ which is less than 85% of theadministered dose and provides improvement in the patient for more than6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration. Inembodiments, provided herein are methods of treating tinnitus includingadministering to a patient in need thereof a pharmaceutical compositionincluding gaboxadol or a pharmaceutically acceptable salt thereofwherein the composition provides an in vivo plasma profile having aAUC₆₋₁₂ which is less than 90% of the administered dose and providesimprovement in the patient for more than 6, 8, 10, 12, 14, 16, 18, 20,22 or 24 hours after administration. In embodiments, provided herein aremethods of treating tinnitus including administering to a patient inneed thereof a pharmaceutical composition including gaboxadol or apharmaceutically acceptable salt thereof wherein the compositionprovides an in vivo plasma profile having a AUC₆₋₁₂ which is less than95% of the administered dose and provides improvement in the patient formore than 6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours afteradministration. In embodiments, provided herein are methods of treatingtinnitus including administering to a patient in need thereof apharmaceutical composition including gaboxadol or a pharmaceuticallyacceptable salt thereof wherein the composition provides an in vivoplasma profile having a AUC₆₋₁₂ which is less than 100% of theadministered dose and provides improvement in the patient for more than6, 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration. Inembodiments, provided herein are methods of treating tinnitus includingadministering to a patient in need thereof a first pharmaceuticalcomposition including gaboxadol or a pharmaceutically acceptable saltthereof and a second pharmaceutical composition including gaboxadol or apharmaceutically acceptable salt thereof wherein the secondpharmaceutical composition provides an in vivo plasma profile having amean AUC_(0-∞) of at least about 20% less than the first pharmaceuticalcomposition.

In embodiments the first and/or the second pharmaceutical compositionsare administered once, twice, or three times daily, or every other day.In embodiments, the first or the second pharmaceutical composition isprovided to the patient in the evening. In embodiments, the secondpharmaceutical composition includes an amount of gaboxadol that is atleast one third of the amount of gaboxadol provided in the firstpharmaceutical composition. In embodiments, the second pharmaceuticalcomposition includes an amount of gaboxadol that is at least half of theamount of gaboxadol provided in the first pharmaceutical composition.

In embodiments, the first or the second pharmaceutical composition isprovided to the patient once in the evening and once in the morning. Inembodiments, the total amount of gaboxadol or pharmaceuticallyacceptable salt thereof administered to a subject in a 24-hour period is1 mg to 30 mg. In embodiments, the total amount of gaboxadol or apharmaceutically acceptable salt thereof administered to a subject in a24-hour period is 1 mg to 20 mg. In embodiments, the total amount ofgaboxadol or a pharmaceutically acceptable salt thereof administered toa subject in a 24-hour period is 10 mg, 15 mg, or 20 mg. In embodiments,the total amount of gaboxadol or a pharmaceutically acceptable saltthereof administered to a subject in a 24-hour period is 20 mg.

In embodiments, the first and/or the second pharmaceutical compositionsmay be provided with immediate release, delayed release, extendedrelease, or modified release profiles. The first and secondpharmaceutical compositions may be provided at the same time orseparated by an interval of time, e.g., 6 hours, 12 hours etc. Inembodiments, the first and the second pharmaceutical compositions may beprovided with different drug release profiles to create a two-phaserelease profile. For example, the first pharmaceutical composition maybe provided with an immediate release profile and the secondpharmaceutical composition may provide an extended release profile. Inembodiments, one or both of the first and second pharmaceuticalcompositions may be provided with an extended release or delayed releaseprofile. Such compositions may be provided as pulsatile formulations,multilayer tablets or capsules containing tablets, beads, granules, etc.In some embodiments, the first pharmaceutical composition is animmediate release composition. In embodiments, the second pharmaceuticalcomposition is an immediate release composition. In embodiments, thefirst and second pharmaceutical compositions are provided as separateimmediate release compositions, e.g., tablets or capsules. Inembodiments the first and second pharmaceutical compositions areprovided 12 hours apart.

In embodiments, provided herein are methods of treating tinnitusincluding administering to a patient in need thereof a firstpharmaceutical composition including gaboxadol or a pharmaceuticallyacceptable salt thereof and a second pharmaceutical compositionincluding gaboxadol or a pharmaceutically acceptable salt thereofwherein the second pharmaceutical composition provides an in vivo plasmaprofile having a mean AUC_(0-∞) of at least about, e.g., 25%, 30%, 35%,40%, 45% or 50% less than the first pharmaceutical composition. Inembodiments, the composition provides improvement in one or moresymptoms of tinnitus a day after administration. For example, thecomposition may provide improvement in one or more symptoms for morethan about, e.g., 6 hours, 8 hours, 10 hours, or 12 hours afteradministration of the first and/or second pharmaceutical composition.

In embodiments, provided herein are methods of treating tinnitusincluding administering to a patient in need thereof a firstpharmaceutical composition including gaboxadol or a pharmaceuticallyacceptable salt thereof and a second pharmaceutical compositionincluding gaboxadol or a pharmaceutically acceptable salt thereofwherein the second pharmaceutical composition provides an in vivo plasmaprofile having a mean AUC_(0-∞) of less than about 900 ng·hr/ml. Inembodiments, the second pharmaceutical composition provides an in vivoplasma profile having a AUC_(0-∞) of less than about, e.g., 800ng·hr/ml, 750 ng·hr/ml, 700 ng·hr/ml, 650 ng·hr/ml, or 600 ng·hr/ml. Inembodiments, the second pharmaceutical composition provides an in vivoplasma profile having a AUC_(0-∞) of less than about, e.g., 550ng·hr/ml, 500 ng·hr/ml, 450 ng·hr/ml, 400 ng·hr/ml, or 350 ng·hr/ml. Inembodiments, the second pharmaceutical composition provides an in vivoplasma profile having a AUC_(0-∞) of less than about, e.g., 300ng·hr/ml, 250 ng·hr/ml, 200 ng·hr/ml, 150 ng·hr/ml, or 100 ng·hr/ml. Inembodiments, the first and second pharmaceutical composition areadministered wherein the compositions provide improvement of next dayfunctioning of the patient. In embodiments, the first pharmaceuticalcomposition provides improvement in one or more symptom for more than,e.g., 6 hours, 8 hours or 12 hours after administration of the firstpharmaceutical composition.

In embodiments, provided herein are methods of treating tinnitusincluding administering to a patient in need thereof a firstpharmaceutical composition including gaboxadol or a pharmaceuticallyacceptable salt thereof and a second pharmaceutical compositionincluding gaboxadol or a pharmaceutically acceptable salt thereofwherein the first composition provides an in vivo plasma profile with aC_(max) that is more than about 50% greater than the C_(max) provided bythe administration of the second pharmaceutical composition. As usedherein the C_(max) provided by the administration of the secondpharmaceutical composition may or may not include the plasma profilecontribution of the first pharmaceutical composition. In embodiments,the administration of the second pharmaceutical composition does notinclude the plasma profile contribution of the first pharmaceuticalcomposition. In embodiments, the first composition provides an in vivoplasma profile having a C_(max) that is more than about e.g., 60%, 70%,80%, or 90% greater than the C_(max) provided by the administration ofthe second pharmaceutical composition.

In embodiments, the T_(max) of the first pharmaceutical composition isless than 3 hours. In embodiments, the T_(max) of the firstpharmaceutical composition is less than 2.5 hours. In embodiments, theT_(max) of the first pharmaceutical composition is less than 2 hours. Inembodiments, the T_(max) of the first pharmaceutical composition is lessthan 1.5 hours. In embodiments, the T_(max) of the first pharmaceuticalcomposition is less than 1 hour.

In embodiments, the first pharmaceutical composition provides adissolution of at least about 80% within the first 20 minutes ofadministration to a patient in need thereof. In embodiments, the firstpharmaceutical composition provides a dissolution of at least about,e.g., 85%, 90% or 95% within the first 20 minutes of administration to apatient in need thereof. In embodiments, the first pharmaceuticalcomposition provides a dissolution of at least 80% within the first 10minutes of administration to a patient in need thereof.

In embodiments the first and/or the second pharmaceutical compositionsare sub therapeutic dosages. A sub therapeutic dosage is an amount ofgaboxadol pharmaceutically acceptable salt thereof that is less than theamount required for a therapeutic effect. In embodiments, a subtherapeutic dosage is an amount of gaboxadol pharmaceutically acceptablesalt thereof that alone may not provide improvement in at least onesymptom of tinnitus but is sufficient to maintain such improvement. Inembodiments, the methods provide administering a first pharmaceuticalcomposition that provides improvement in at least one symptom oftinnitus and a second composition that maintains the improvement. Inembodiments, after administration of the first pharmaceuticalcomposition the second pharmaceutical composition may provide asynergistic effect to improve at least one symptom of tinnitus. Inembodiments the second pharmaceutical composition may provide asynergistic effect to improve at least one symptom of tinnitus.

In embodiments, provided herein are methods of treating tinnitusincluding administering to a patient in need thereof a pharmaceuticalcomposition including a first pharmaceutical dosage including gaboxadolor a pharmaceutically acceptable salt thereof wherein the compositionprovides improvement for more than 6 hours after administration and asecond pharmaceutical composition including a sub therapeutic dosage ofgaboxadol or a pharmaceutically acceptable salt thereof.

Administration of the first and second pharmaceutical compositions maybe separated by an interval of time to achieve long-term improvement inat least one symptom of tinnitus. In embodiments, the first and secondpharmaceutical composition may be administered 6 hours apart. Inembodiments the first and second pharmaceutical composition may beadministered 12 hours apart. In embodiments, the first and secondpharmaceutical compositions may administered within, e.g., 6 hours, 12hours, 18 hours, 24 hours etc. In embodiments, the first and secondpharmaceutical compositions may administered separated by at least,e.g., 6 hours, 12 hours, 18 hours, 24 hours etc. In embodiments,improvement in at least one symptom of tinnitus for more than 8 hoursafter administration to the patient is provided. In embodiments,improvement for more than about, e.g., 10 hours, 12 hours, 15 hours, 18hours, 20 hours, or 24 hours after administration to the patient isprovided.

In embodiments, the first pharmaceutical composition and/or the secondpharmaceutical composition include about 0.1 mg to about 40 mg gaboxadolor a pharmaceutically acceptable salt thereof. The amount of gaboxadolor a pharmaceutically acceptable salt thereof in the firstpharmaceutical composition and the second pharmaceutical composition maybe the same or different. In embodiments, the administration of thefirst and second pharmaceutical composition may provide a synergisticeffect to improve at least one symptom of tinnitus.

In embodiments, the first and/or the second pharmaceutical compositioninclude 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.5 mg to 25mg, 0.5 mg to 20 mg, 0.5 to 15 mg, 1 mg to 25 mg, 1 mg to 20 mg, 1 mg to15 mg, 1.5 mg to 25 mg, 1.5 mg to 20 mg, 1.5 mg to 15 mg, 2 mg to 25 mg,2 mg to 20 mg, 2 mg to 15 mg, 2.5 mg to 25 mg, 2.5 mg to 20 mg, 2.5 mgto 15 mg, 3 mg to 25 mg, 3 mg to 20 mg, or 3 mg to 15 mg gaboxadol or apharmaceutically acceptable salt thereof.

In embodiments, the first and/or the second pharmaceutical compositioninclude 5 mg to 15 mg, 5 mg to 10 mg, 4 mg to 6 mg, 6 mg to 8 mg, 8 mgto 10 mg, 10 mg to 12 mg, 12 mg to 14 mg, 14 mg to 16 mg, 16 mg to 18mg, or 18 mg to 20 mg gaboxadol or a pharmaceutically acceptable saltthereof.

In embodiments, the first and/or the second pharmaceutical compositioninclude 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7 mg,7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg gaboxadol or apharmaceutically acceptable salt thereof or amounts that are multiplesof such doses. In embodiments, the first pharmaceutical compositionsinclude 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, or 20 mg gaboxadol or apharmaceutically acceptable salt thereof. In embodiments, the secondpharmaceutical compositions include 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg,or 20 mg gaboxadol or a pharmaceutically acceptable salt thereof.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of skill in the artto which the disclosure herein belongs.

The term “about” or “approximately” as used herein means within anacceptable error range for the particular value as determined by one ofordinary skill in the art, which will depend in part on how the value ismeasured or determined, i.e., the limitations of the measurement system.For example, “about” can mean within 3 or more than 3 standarddeviations, per the practice in the art. Alternatively, “about” can meana range of up to 20%, up to 10%, up to 5%, and/or up to 1% of a givenvalue. Alternatively, particularly with respect to biological systems orprocesses, the term can mean within an order of magnitude, preferablywithin 5-fold, and more preferably within 2-fold, of a value.

“Improvement” refers to the treatment of tinnitus measured relative toat least one symptom.

“Improvement in one or more symptoms of tinnitus a day afteradministration” refers to improvement wherein the beneficial effect ofat least one symptom lasts over a period of time, e.g., 6 hours, 12hours, 24 hours etc.

“PK” refers to the pharmacokinetic profile. C_(max) is defined as thehighest plasma drug concentration estimated during an experiment(ng/ml). T_(max) is defined as the time when C_(max) is estimated (min).AUC_(0-∞) is the total area under the plasma drug concentration-timecurve, from drug administration until the drug is eliminated (ng·hr/ml).The area under the curve is governed by clearance. Clearance is definedas the volume of blood or plasma that is totally cleared of its contentof drug per unit time (ml/min).

“Treating” or “treatment” refers to alleviating or delaying theappearance of clinical symptoms of a disease or condition in a subjectthat may be afflicted with or predisposed to the disease or condition,but does not yet experience or display clinical or subclinical symptomsof the disease or condition. In certain embodiments, “treating” or“treatment” may refer to preventing the appearance of clinical symptomsof a disease or condition in a subject that may be afflicted with orpredisposed to the disease or condition, but does not yet experience ordisplay clinical or subclinical symptoms of the disease or condition.“Treating” or “treatment” also refers to inhibiting the disease orcondition, e.g., arresting or reducing its development or at least oneclinical or subclinical symptom thereof. “Treating” or “treatment”further refers to relieving the disease or condition, e.g., causingregression of the disease or condition or at least one of its clinicalor subclinical symptoms. The benefit to a subject to be treated may bestatistically significant, mathematically significant, or at leastperceptible to the subject and/or the physician. Nonetheless,prophylactic (preventive) and therapeutic (curative) treatment are twoseparate aspects of the disclosure herein.

“Pharmaceutically acceptable” refers to molecular entities andcompositions that are “generally regarded as safe”—e.g., that arephysiologically tolerable and do not typically produce an allergic orsimilar untoward reaction, such as gastric upset and the like, whenadministered to a human. In embodiments, this term refers to molecularentities and compositions approved by a regulatory agency of the federalor a state government, as the GRAS list under section 204(s) and 409 ofthe Federal Food, Drug and Cosmetic Act, that is subject to premarketreview and approval by the FDA or similar lists, the U.S. Pharmacopeiaor another generally recognized pharmacopeia for use in animals, andmore particularly in humans.

“Effective amount” or “therapeutically effective amount” means a dosagesufficient to alleviate one or more symptoms of a disorder, disease, orcondition being treated, or to otherwise provide a desiredpharmacological and/or physiologic effect.

“Patient in need thereof” includes individuals that have been diagnosedtinnitus. The methods may be provided to any individual including, e.g.,wherein the patient is a neonate, infant, a pediatric patient (6 monthsto 12 years), an adolescent patient (age 12-18 years) or an adult (over18 years).

EXAMPLES

The Examples provided herein are included solely for augmenting thedisclosure herein and should not be considered to be limiting in anyrespect.

Example 1

The following Example provides the plasma concentration profiles anddose proportionality of gaboxadol monohydrate following single oraldoses ranging from 2.5 to 20 mg. The absolute bioavailability ofgaboxadol monohydrate capsules ranging from 2.5 to 20 mg is alsoassessed.

This study was composed of separate groups of 10 healthy adult subjects(at least 4 of each gender) who participated in a 6-period,double-blind, randomized, crossover study designed to access the doseproportionality and absolute bioavailabilty of 5 single oral doses ofgaboxadol across the dose range of 2.5 to 20 mg. The order in which thesubjects received the 5 single oral doses of gaboxadol (2.5; 5; 10; 15;and 20 mg) was randomized within Treatment Periods 1 through 5. Eachsubject was expected to complete all 6 treatment periods and there was awashout of at least 4 days between each treatment period.

Each oral dosing within Treatment Periods consisted of 2 capsules oftest drug taken simultaneously at each scheduled dosing. The treatmentdesignations for the orally administered study drugs were as follows:Treatment A—one 2.5 mg gaboxadol capsule and 1 matching placebo capsule;Treatment B—one 5 mg gaboxadol capsule and 1 matching placebo capsule;Treatment C—one 10 mg gaboxadol capsule and 1 matching placebo capsule;Treatment D—one 15 mg gaboxadol capsule and 1 matching placebo capsule;and Treatment E—20 mg gaboxadol (two 10 mg gaboxadol capsules). Subjectsreceived their study drug after an overnight fast with 240 mL of waterin the morning about 8:00 AM. Water was permitted ad libitum exceptwithin 1 hour prior to and after study drug administration. No food wasallowed for 4 hours post dose.

For each subject in each treatment, plasma and urine samples werecollected over 16 hours post-dosing for the determination ofpharmacokinetic parameters (e.g., AUC, C_(max), T_(max), apparent t½,cumulative urinary excretion, renal clearance, clearance, andsteady-state volume of distribution, as appropriate). AUC and C_(max)for gaboxadol were potency adjusted to facilitate comparison ofpharmacokinetic data across studies. Table 1 provides the individualpotency-adjusted pharmacokinetic parameters of gaboxadol followingsingle oral doses (2.5, 5, 10, 15, and 20 mg).

TABLE 1 Pharmacokinetic parameters for gaboxadol following oral and IVadministration Geometric Mean (N = 10) 10 mg 10 mg Parameter 2.5 mg 5 mgOral I.V. 15 mg 20 mg Slope (90% CI)†† AUC_(0-∞) (ng · hr/mL) 90 171 346380 539 669 0.98 (0.95, 1.01) C_(max) (ng/mL)^(†) 61 110 232 212 382 3930.95 (0.88, 1.02) T_(max) (hr)^(‡) 0.5 0.6 0.5 — 0.5 0.6 Apparentt_(1/4) (hr)^(§) 1.5 1.5 1.6 1.5 1.5 1.6

CL/F (mL/min)¶ 461 488 476 438 469 499 f_(c)(%) 43 45 53 53 50 53 CL_(R)(mL/min) 196 222 250 208 234 265 F (%) (90% CI)# 92% (0.86, 0.97)^(†)C(ng/mL) for 10 mg IV. ‡Median. ^(§)Harmonic Mean.

CL (mL/min) for 10 mg IV. #Bioavailability relative to 10 mg I.V.reference based on pooled dose adjusted (to 10 mg) oral AUC_(0-∞)values. ††Dose proportionality assessment of oral treatments only.

FIG. 2 shows the arithmetic mean plasma concentration-time profiles ofgaboxadol following single oral doses (2.5, 5, 10, 15, and 20 mg). Thebioavailability of gaboxadol is approximately 92%. Plasma AUC_(0-∞) andC_(max) of gaboxadol show dose proportional increases and appear to belinear over the entire dose range examined, from of 2.5 to 20 mg. Thetime to peak plasma concentrations (T_(max) 30-60 min) and the half-life(t½ of 1.5 h) for gaboxadol appear to be independent of dose across thegaboxadol dose range of 2.5 to 20 mg. The excretion of gaboxadol ismainly via urine, where 96.5% of the dose is recovered; 75% is recoveredwithin 4 hours after administration.

Example 2 Assessment of Residual Effects Resulting from GaboxadolAdministration

This study was a double blind, double-dummy, randomized, active- andplacebo-controlled, single dose, 3-period crossover study, followed byan open-label, single-dose, single period study in healthy elderly maleand female subjects. Subjects were randomized to each of 3 treatments(Treatments A, B, and C) to be administered in a crossover manner overthe first 3 treatment periods. For Treatment A, subjects received asingle dose of gaboxadol 10 mg; for Treatment B, subjects received asingle dose of flurazepam 30 mg; and for Treatment C, subjects receiveda single dose of placebo. Doses were administered orally at bedtime onDay 1. Subjects were domiciled from early in the evening of dosing until˜36 hours post-dose (morning of Day 3) during each treatment period. Thesubjects who participated in treatment periods 1-3 participated in afourth treatment period. In this period, a single dose of gaboxadol 10mg (Treatment D) was administered orally in an open-label manner on themorning of Day 1 for PK of gaboxadol. There was at least a 14-daywashout between the doses of consecutive treatment periods. Studyparticipants included healthy, elderly male and female subjects between65 and 80 years of age, with a Mini Mental Status 24, weighing at least55 kg.

All subjects received 10 mg gaboxadol monohydrate capsules and 30 mgflurazepam (provided as 2×15 mg capsules), matching placebo was providedfor both gaboxadol and flurazepam.

The primary endpoints evaluated included pharmacodynamics (measurementof psychomotor performance, memory, attention and daytime sleepiness thefollowing pm dosing), gaboxadol pharmacokinetics, and safety. Gaboxadol(single dose 10 mg) did not show residual effect 9 hours post-dose onthe primary endpoints Choice Reaction Time and Critical Flicker Fusion,whereas the active reference Flurazepam (30 mg single dose) showedsignificant effect on the same tests. In addition, gaboxadol did notshow any signs of residual effects on other measurements applied in thestudy (Multiple Sleep Latency Test (MSLT); Digit symbol substitutiontest (DSST), Tracking, Memory tests, Body Sway, and Leeds SleepEvaluation Questionnaire).

Example 3 Study of Driving Performance after Gaboxadol Administration

This study was a double blind, randomized, placebo and active controlled5 way cross over study to investigate the effect of evening and middleof the night dosing of gaboxadol on driving performance. The studyparticipants included healthy, male and female subjects between 21 and45 years of age, with a valid drivers license for at least 3 years.

The effects of gaboxadol on driving performance were investigated usingreal driving on the road setting. Subjects received 15 mg gaboxadoleither in the evening prior to going to bed or at 4 am in the middle ofthe night following a wake-up call. Following a cognitive andpsychomotor test battery, the driving test started at 9 am and lastedfor one hour. Gaboxadol 15 mg had a clinically relevant impairing effecton driving following middle-of-the-night administration.

Following the evening dose, a statistically significant effect ofgaboxadol 15 mg was observed on driving. However, this effect was lessthan the effect observed at a 0.05% blood alcohol concentration, theconcentration limit at which driving is prohibited in most Europeancountries. There was generally a numerically greater effect followingzopiclone (7.5 mg) and zolpidem (10 mg) administered in the evening andin the middle of the night, respectively. Both the evening and themiddle-of-the-night dose of gaboxadol were well tolerated with the mostfrequent adverse events being dizziness, nausea and somnolence for themiddle-of-the-night treatment and headache and somnolence for theevening treatment.

Subjects on the active reference zopiclone had a numerically greatereffect in the same test. There was no effect on memory test, body sway,DSST or critical tracking, whereas zopiclone had effect on several ofthese tests.

Example 4 Study of Daytime Performance after Sleep Restriction

This study was a 4-night, parallel-group, randomized, double-blind (within-house blinding), placebo-controlled, fixed-dose study to assess theeffects of gaboxadol on daytime performance in healthy adults subjectedto a 5-hour sleep restriction. The study included a 2-night single-blindplacebo run-in period, a 4-night double-blind treatment period duringwhich sleep was restricted to 5 hours and a 2-night single-blind placeborun-out period. The study included healthy male and female volunteers 18to <55 years of age.

2-night run-in period: All patients received placebo

4-night double-blind treatment period: Patients were randomized togaboxadol 15 mg or matching placebo

2-night run-out period: All patients received placebo

The primary endpoints included observations based on the Multiple SleepLatency Test (MSLT) and Slow Wave Sleep (SWS) assessment. The primaryobjective was to evaluate the efficacy of gaboxadol (15 mg) compared toplacebo in reducing daytime sleep propensity as measured by MSLT. Thegaboxadol subjects had significantly less daytime sleepiness during theSleep Restriction period than did placebo subjects (p=0.047, 1 sided).The MSLT was on average 2.01 minutes longer for subjects treated withgaboxadol (15 mg) than for those with placebo on the last two SleepRestriction days.

In addition, a secondary objective was to evaluate the efficacy ofgaboxadol compared to placebo in increasing the amount of slow wavesleep (SWS) during the last 2 nights of sleep restriction. Subjectsreceiving gaboxadol experienced significantly more SWS during the SleepRestriction period than did placebo subjects (p<0.001, 1 sided).

Moreover, subjects treated with gaboxadol on average had 20.53 minutesof SWS longer than those treated with placebo on the last two SleepRestriction nights.

Finally, this study examined the efficacy of gaboxadol compared toplacebo during the last 2 nights/days of sleep restriction in: (1)improving memory and attention as assessed by a neurobehavioral battery;(2) reducing subjective sleepiness as measured by the KarolinskaSleepiness Score (KSS); (3) altering sleep parameters (e.g., total sleeptime, latency to onset of Slow Wave Sleep (SWS), slow wave activity(SWA); and (4) reducing biological stress typified by increased heartrate variability, and decreased cortisol levels and decreasedcatecholamine levels, as well as decreased body temperature.

There was a trend towards less subjective daytime sleepiness for thegaboxadol subjects during the Sleep Restriction period as compared withplacebo subjects. The Karolinska Sleepiness Score (KSS) was on average0.68 less for subjects treated with gaboxadol than for those treatedwith placebo on the last two Sleep Restriction days (p=0.058, 1 sided)as evaluated by a Longitudinal data analysis (LDA) model with adjustmentfor baseline KSS, gender, and age. A supportive analysis usingcovariance (ANCOVA) also supports this finding. The effect sizescomputed for the neurocognitive battery showed that there was no strongevidence that gaboxadol improves daytime performance. There were nodifferences between gaboxadol and placebo with respect tobiophysiological measures of stress (heart rate variability, cortisollevels, catecholamine levels, body temperature).

Compared with placebo, gaboxadol has a protective effect on reducingdaytime sleepiness as measured by the MSLT on the last 2 days of4-nights of sleep restriction. Compared with placebo, gaboxadolincreases the amount of slow wave sleep (SWS) during the last 2 nightsof 4-nights of sleep restriction.

Example 5 Prospective Assessment of the Efficacy of Gaboxadol inPatients with Tinnitus

This study is designed to determine whether gaboxadol leads to animprovement in tinnitus. The primary objective of this study may be toevaluate the safety and tolerability from Baseline to Week 6 and Week 12of gaboxadol in adult subjects with tinnitus across different doselevels and in two dosing schedules. The following dosing schedules maybe tested against placebo: (1) Once daily (o.d.): An evening dose,titrated to the target dose of 15 mg unless not tolerated; and (2) Twicedaily (b.i.d.): Evening and morning doses titrated to the target dosesof 15 mg evening dose and 10 mg morning dose unless not tolerated.

The Safety endpoints that relate to this study may include: (1)Frequency and severity of adverse events (AEs) and serious adverseevents; (2) Vital signs (weight, blood pressure, temperature); (3)Laboratory parameters (electrolytes, lipids, glucose, liver and pancreasfunction tests, hematology, creatinine); (4) Suicidality assessed byABC-Irritability Subscale; (5) EEG (change in background frequency,intensity of epileptiform discharges); and/or (6) Caregivers maymaintain an electronic seizure diary (on same device as sleep log).

The secondary objective of this study may include the identification ofa set of parameters that may best characterize the efficacy of gaboxadolin adult tinnitus subjects for subsequent efficacy trials. These testsmay be administered at four full day site visits (Screening, Baseline,Interim and End of Treatment) by an appropriately trained professionalto provide the test to an adult tinnitus patient. Assessments may bebased on patient's perception of symptoms. Tinnitus loudness-visualanalogue scale (VAS) [Time Frame: each week: the time between thequestionnaire results at the beginning and compared to the results aftereach week following initial administration. Tinnitus loudness scale: Arange of 1-10 scale. the patients choose which number reflects theloudness of the subjective tinnitus which the patients suffer from. thehigher the number-the louder the tinnitus. Tinnitus suffer scale: Arange of 1-10 scale. the patient choose which number reflects the bestthe degree in which the tinnitus causes the patient to suffer. thehigher the score-the worse is the tinnitus.

Evaluation of sleep may include analysis by actigraphy to measure: (1)Sleep Onset Latency (SOL); (2) Total Sleep Time (TST); (3) Wake AfterSleep Onset (WASO)=total # of wake epochs after sleep onset; (4)Nocturnal Awakenings (NA); and/or (5) Sleep Efficiency=total sleep time(TST) of time in bed (TIB). Additional evaluation of sleep may includeanalysis of parent/caregiver logs of sleep patterns that may include:(1) bed time; (2) time of sleep onset; (3) number and duration ofawakenings; (4) number of disruptive behavior; (5) time of lastawakening; and (6) daytime sleepiness.

This study may include three treatment groups. For example, a total ofapproximately 75 subjects may be enrolled and at the completion of thestudy, there may be approximately 25 subjects in each of the threetreatment groups: 1) single evening dose 2) morning and evening dose and3) placebo.

All subjects may receive a morning dose (either active or placebo) andan evening dose (either active or placebo) during the entire duration oftreatment. For example, as illustrated in FIG. 3, two dosing schedulesof gaboxadol may be tested: a single evening dose (o.d.; Schedule A) anda morning plus evening dose (b.i.d; Schedule B) designed to provide amore sustained exposure. Schedule C is morning and evening placebo. Allsubjects may be up-titrated to the target dose unless this target doseis not tolerated (titration conventions described below). All subjectsmay receive treatment for a maximum of 12 weeks at their optimaltolerated dose.

Doses may be progressively increased in 5 mg increments (active orplacebo) to a target dose of 3 capsules evening dose in schedule A andB, and 2 capsules morning dose in schedule B. Each dose escalation maybe performed after adequate tolerability has been assessed by caregiverand investigator. For example, treatment initiation at Day 1 with 1capsule (active (Act) or placebo (Plc)) in the evening. Then targetup-titration may begin at Day 3 (window+2 days): If no adverse event(AE) related to the study drug is observed by caregiver and/or theinvestigator, another capsule (active or placebo) is added in theevening. Again at Day 7 (window+2 days), Day 10 (window+2 days and Day14 (window+2 days) if no AE related to the study drug is observed bycaregiver and/or the investigator, another capsule (active or placebo)may be added in the morning. Table II below provides a graphicillustration of the titration schedule.

TABLE II Titration Schedule Schedule/Time Days 1 to 2 Days 3 to 6 Days 7to 9 Days 10 to 13 Day 14* Schedule A Evening 5 mg 10 mg 15 mg 15 mg 15mg 1 Capsule  2 Capsules  3 Capsules  3 Capsules  3 Capsules MorningNone None None Placebo Placebo  1 Capsule  2 Capsules Schedule B Evening5 mg 10 mg 15 mg 15 mg 15 mg 1 Capsule  2 Capsules  3 Capsules  3Capsules  3 Capsules Morning None None None  5 mg 10 mg  1 Capsule  2Capsules Schedule C Evening Placebo Placebo Placebo Placebo Placebo 1Capsule  2 Capsules  3 Capsules  3 Capsules  3 Capsules Morning NoneNone None Placebo Placebo  1 Capsule  2 Capsules *To end of studytreatment period

Slowed up-titration or delayed up-titration will be acceptable iftolerability does not allow immediate further dose-escalation at any ofthe above detailed days (3, 7, 10, 14). Down-titration in the casetolerability is not acceptable (e.g., somnolence, dizziness, change inbehavior) after a previous up-titration step or during the course of the12 week treatment, dose can be reduced to the previous level or evenfurther. However, once a tolerable dose has been reached, it shallremain constant for the duration of the treatment period. Once a targetdose is achieved the treatment may continue. For example, at Day 14:Earliest day the target dose can be reached (2 capsules in the morningand 3 in the evening) the subject may be kept stable until End ofTreatment visit (week 12) unless intolerability requires down-titration.

All subjects will be screened for participation in the study up to 28days prior to the first dose administration. Inclusion criteria mayinclude one or more of the following: (1) Age ≥18 years, ≤40 years; (2)Must possess a clinical diagnosis of tinnitus. Descriptive statisticsmay be used to summarize all primary and secondary endpoints as well asbaseline variables, by treatment group. For continuous variables, n,number of missing values, mean, standard deviation, median, minimum, andmaximum will be provided. For categorical variables, frequency andpercentage will be presented for each category. Confidence intervals(CI) will be provided where meaningful. All CIs will be two-sided 95%confidence intervals.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments described herein. Such equivalents are intended to beencompassed by the claims.

What is claimed is:
 1. A method of treating tinnitus comprisingadministering to a patient in need thereof about 0.05 mg to about 30 mggaboxadol or a pharmaceutically acceptable salt thereof, wherein themethod provides improvement in one or more symptoms of tinnitus in thepatient and the improvement is provided for more than 6 hours afteradministration.
 2. The method of claim 1, wherein the patient isadministered a composition comprising about 1 mg to about 15 mggaboxadol or a pharmaceutically acceptable salt thereof.
 3. The methodof claim 1, wherein the patient is administered a composition comprisingabout 1 mg to about 10 mg gaboxadol or a pharmaceutically acceptablesalt thereof.
 4. The method of claim 1, wherein the patient isadministered a composition comprising about 1 mg to about 5 mg gaboxadolor a pharmaceutically acceptable salt thereof.
 5. The method of claim 1,wherein the in vivo plasma profile of the patient 6 hours afteradministration of the gaboxadol or pharmaceutically acceptable saltthereof is reduced by more than 50%.
 6. The method of claim 1, whereinthe AUC₆₋₁₂ of the patient 6 hours after administration of the gaboxadolor pharmaceutically acceptable salt thereof is less than 75% of theadministered dose.
 7. The method of claim 1, wherein the method providesimprovement in at least one symptom selected from the group consistingof ringing, roaring, static, buzzing, hissing, whooshing, cricketnoises, jackhammer noises and whistling, in one or both ears.
 8. Themethod of claim 1, wherein the method provides improvement in thepatient for more than 8 hours.
 9. The method of claim 1, wherein thecomposition provides improvement in the patient for at least 12 hours.10. The method of claim 1, further comprising administering from about 1mg to about 30 mg clobazam or a pharmaceutically acceptable salt thereofto the patient.
 11. The method of claim 12, wherein the amount ofclobazam or a pharmaceutically acceptable salt thereof is 5 mg to 20 mg.12. The method of claim 13, wherein the amount of clobazam or apharmaceutically acceptable salt thereof is 10 mg.
 13. A method oftreating acute sensorineural hearing loss comprising administering to apatient in need thereof gaboxadol or a pharmaceutically acceptable saltthereof wherein the method provides an in vivo plasma profile comprisinga C_(max) less than about 400 ng/ml and wherein the method providesimprovement in the patient for more than 6 hours after administration ofthe gaboxadol or a pharmaceutically acceptable salt thereof.
 14. Amethod of treating acute sensorineural hearing loss comprisingadministering to a patient in need thereof gaboxadol or apharmaceutically acceptable salt thereof wherein the method provides anin vivo plasma profile comprising a AUC₆₋₁₂ of less than about 900ng·hr/ml and wherein the method provides improvement in the patient formore than 6 hours after administration of the gaboxadol or apharmaceutically acceptable salt thereof.
 15. The method of claim 1wherein the method provides improvement in the patient for more than aday after administration.